GAPDH facilitates homologous recombination repair by stabilizing RAD51 in an HDAC1-dependent manner.

Homologous recombination (HR), a form of error-free DNA double-strand break (DSB) repair, is important for the maintenance of genomic integrity. Here, we identify a moonlighting protein, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), as a regulator of HR repair, which is mediated through HDAC1-dependent regulation of RAD51 stability. Mechanistically, in response to DSBs, Src signaling is activated and mediates GAPDH nuclear translocation. Then, GAPDH directly binds with HDAC1, releasing it from its suppressor. Subsequently, activated HDAC1 deacetylates RAD51 and prevents it from undergoing proteasomal degradation. GAPDH knockdown decreases RAD51 protein levels and inhibits HR, which is re-established by overexpression of HDAC1 but not SIRT1. Notably, K40 is an important acetylation site of RAD51, which facilitates stability maintenance. Collectively, our findings provide new insights into the importance of GAPDH in HR repair, in addition to its glycolytic activity, and they show that GAPDH stabilizes RAD51 by interacting with HDAC1 and promoting HDAC1 deacetylation of RAD51.

Excessive iron inhibits insulin secretion via perturbing transcriptional regulation of SYT7 by OGG1.

Although iron overload is closely related to the occurrence of type 2 diabetes mellitus (T2DM), the specific mechanism is unclear. Here, we found that excessive iron inhibited the secretion of insulin (INS) and impaired islet ß cell function through downregulating Synaptotagmin 7 (SYT7) in iron overload model in vivo and in vitro. Our results further demonstrated that 8-oxoguanine DNA glycosylase (OGG1), a key protein in the DNA base excision repair, was an upstream regulator of SYT7. Interestingly, such regulation could be suppressed by excessive iron. Ogg1-null mice, iron overload mice and db/db mice exhibit reduced INS secretion, weakened ß cell function and subsequently impaired glucose tolerance. Notably, SYT7 overexpression could rescue these phenotypes. Our data revealed an intrinsic mechanism by which excessive iron inhibits INS secretion through perturbing the transcriptional regulation of SYT7 by OGG1, which suggested that SYT7 was a potential target in clinical therapy for T2DM.

Polß modulates the expression of type I interferon via STING pathway.

DNA Polymerase ß (Polß) is a key enzyme in base excision repair (BER), which is very important in maintaining the stability and integrity of the genome. Mutant Polß is closely associated with carcinogenesis. However, Polß is highly expressed in most cancers, but the underlying mechanism is not well understood. Here, we found that breast cancer cells MCF-7 with Polß knockdown exhibited high levels of type I interferon and were easily eliminated by natural killer (NK) cells.Similarly, Polß-mutant (R137Q) mice exhibited chronic inflammation symptoms in multiple organs and upregulated type I interferon levels. Further results showed that Polß deficiency caused more DNA damage accumulation in cells and triggered the leakage of damaged DNA into the cytoplasm, which activated the STING/IRF3 pathway, promoted phosphorylated IRF3 translocating into the nucleus and enhanced the expression of type I interferon and proinflammatory cytokines. In addition, this effect could be eliminated by Polß overexpression, STING inhibitor or STING knockdown. Taken together, our findings provide mechanistic insight into the role of Polß in cancers by linking DNA repair and the inflammatory STING pathway.

Adipocyte-specific deletion of PIP5K1c reduces diet-induced obesity and insulin resistance by increasing energy expenditure.

BACKGROUND: Phosphatidylinositol 4-phosphate 5-kinase type I c (PIP5K1c) catalyses the synthesis of phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) by phosphorylating phosphatidylinositol 4 phosphate, which plays multiple roles in regulating focal adhesion formation, invasion, and cell migration signal transduction cascades. Here, a new physiological mechanism of PIP5K1c in adipocytes and systemic metabolism is reported. METHODS: Adipose-specific conditional knockout mice were generated to delete the PIP5K1c gene in adipocytes. In addition, in vitro research investigated the effect of PIP5K1c deletion on adipogenesis. RESULTS: Deletion of PIP5K1c in adipocytes significantly alleviated high fat diet (HFD)-induced obesity, hyperlipidaemia, hepatic steatosis, and insulin resistance. PIP5K1c deficiency in adipocytes also decreased adipocyte volume in HFD-induced obese mice, whereas no significant differences were observed in body weight and adipose tissue weight under normal chow diet conditions. PIP5K1c knockout in adipocytes significantly enhanced energy expenditure, which protected mice from HFD-induced weight gain. In addition, adipogenesis was markedly impaired in mouse stromal vascular fraction (SVF) from PIP5K1c-deleted mice. CONCLUSION: Under HFD conditions, PIP5K1c regulates adipogenesis and adipose tissue homeostasis. Together, these data indicate that PIP5K1c could be a novel potential target for regulating fat accumulation, which could provide novel insight into the treatment of obesity.

Achieving Efficient Multichannel Conductance in Through-Space Conjugated Single-Molecule Parallel Circuits.

Constructing single-molecule parallel circuits with multiple conduction channels is an effective strategy to improve the conductance of a single molecular junction, but rarely reported. We present a novel through-space conjugated single-molecule parallel circuit (f-4Ph-4SMe) comprised of a pair of closely parallelly aligned p-quaterphenyl chains tethered by a vinyl bridge and end-capped with four SMe anchoring groups. Scanning-tunneling-microscopy-based break junction (STM-BJ) and transmission calculations demonstrate that f-4Ph-4SMe holds multiple conductance states owing to different contact configurations. When four SMe groups are in contact with two electrodes at the same time, the through-bond and through-space conduction channels work synergistically, resulting in a conductance much larger than those of analogous molecules with two SMe groups or the sum of two p-quaterphenyl chains. The system is an ideal model for understanding electron transport through parallel π-stacked molecular systems and may serve as a key component for integrated molecular circuits with controllable conductance.

Do multiple environmental factors impact four cancers in women in the contiguous United States?

BACKGROUND: Though there has been an increasing concern about the effects that environmental exposures have on cancer, limited knowledge exists regarding multiple environmental factors on cancers in women. METHODS: We performed a spatial autoregressive model to examine the association between the Environmental Quality Index (EQI) and mortalities of four cancers in women (breast, cervical, ovarian and uterine cancer) based on county-level data, and explored these associations by urbanicity. The EQI, which included five domains (air, water, land, built environment and sociodemographic domain) estimated from 2000 to 2005 data, was obtained from the United States Environmental Protection Agency. The mortality rates for 3107 counties in the US in 2014 were obtained from the Institute for Health Metrics and Evaluation. RESULTS: We found that each unit increase in the overall EQI was positively associated with the increased mortality of breast, ovarian and uterine cancer (2.5%, 3.6% and 3.1% respectively), but was negatively associated with cervical cancer mortality. Among the environmental domains, the air and sociodemographic EQIs were positively associated with increased risks of breast, ovarian and uterine cancers. Additionally, built environment EQI was associated with breast and ovarian cancers; land EQI was associated with uterine and ovarian cancers. The sociodemographic EQI was negatively associated with cervical cancer mortality. Furthermore, we have developed a novel Environmental Quality Health Index (EQHI) in identifying environment-health risk of cancers in women at county level. CONCLUSIONS: Our findings suggest that breast, ovarian, and uterine cancer mortalities are positively associated with multiple environmental factors, while cervical cancer mortality is mainly negatively associated with sociodemographic factors. The novel EQHI might help identify spatially-based environment-cancer risk.

Conductance Measurement of Pyrazine Molecular Junction with Cu and Ag Electrodes.

We have measured the conductance of pyrazine molecular junction contacting with Cu and Ag electrodes by using an electrochemical jump-to-contact based scanning tunneling microscopy break junction (ECSTM-BJ). While conductance values of 10-2.8 and 10-3.7 G0 are measured for pyrazineCu electrode, 10-2.1 and 10-3.3 G0 are found for pyrazine-Ag contact. The result shows that the conductance of pyrazine with Ag electrode is larger than that with Cu electrode, which can contribute to the different efficiency of electron transport along the molecular junction between Ag and Cu electrodes. The current work shows the important role for the electrode material in electron transport.

Determination of corypalmine in mouse blood by UPLC-MS/MS and its application to a pharmacokinetic study.

In this work, a selective and sensitive ultra-performance liquid chromatography tandem mass spectrometry method was established and validated for determination of corypalmine in mouse blood after oral or intravenous administration. A UPLC BEH C18 column was used to separate corypalmine and berberrubine (internal standard) at 40°C. The mobile phase was composed of acetonitrile and 10 mmol/L ammonium acetate (containing 0.1% formic acid) at a flow rate of 0.4 mL/min, and the total run time was 4.0 min. Electrospray ionization in positive ion mode was applied; target fragment ions m/z 342.2 → 178.0 for corypalmine and m/z 322.1 → 307.0 for berberrubine were identified with multiple reaction monitoring mode. The linear range was 1-1000 ng/mL (r > 0.995) and the lower limit of quantification for corypalmine in plasma was 1.0 ng/mL. The intra- and inter-day precisions were both <14%. The range of accuracy in this method was 97.5-109.0%. Mean recovery was >69.6%, and the matrix effect was 96.8-107.6%. Based on its high sensitivity, specificity and reliability, this method was successfully applied to study the pharmacokinetic parameters of corypalmine in mouse by oral and intravenous administration, and finally, the bioavailability of corypalmine was identified at 4.6%.

Detecting Electron Transport of Amino Acids by Using Conductance Measurement.

The single molecular conductance of amino acids was measured by a scanning tunneling microscope (STM) break junction. Conductance measurement of alanine gives out two conductance values at 10-1.85 G0 (1095 nS) and 10-3.7 G0 (15.5 nS), while similar conductance values are also observed for aspartic acid and glutamic acid, which have one more carboxylic acid group compared with alanine. This may show that the backbone of NH2-C-COOH is the primary means of electron transport in the molecular junction of aspartic acid and glutamic acid. However, NH2-C-COOH is not the primary means of electron transport in the methionine junction, which may be caused by the strong interaction of the Au-SMe (methyl sulfide) bond for the methionine junction. The current work reveals the important role of the anchoring group in the electron transport in different amino acids junctions.

Association Between HIF-1 Alpha Gene Polymorphisms and Response in Patients Undergoing Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer.

BACKGROUND The aim of the study was to assess whether HIF-1α polymorphisms have an effect on the response to chemotherapy of locally advanced cervical cancer (LACC) patients treated with platinum-based neoadjuvant chemotherapy (NACT) and radical surgery. MATERIAL AND METHODS We conducted a retrospective study in 162 LACC patients. Hypoxia-inducible factor 1α C1772T and G1790A genetic polymorphisms were ascertained using direct sequencing methods. RESULTS The C1772T polymorphism was significantly related to response to chemotherapy (P=0.002), and there was an increased chance of treatment response in patients with the C/C genotype (OR=4.7; 95% CI: 1.67-13.49; P=0.004). The C1772T polymorphism was also associated with poor tumor grade (adjusted OR, 2.98; 95% CI: 1.08-8.13; P=0.037). However, The G1790A polymorphism was not associated with response (P>0.05). CONCLUSIONS The C1772T polymorphism was significantly related to response to chemotherapy and poor tumor grade. Our results may help to better manage individual patients and to improve clinical decision making regarding use of NACT.

Overexpression of hypoxia-inducible factor-1α is a predictor of poor prognosis in cervical cancer: a clinicopathologic study and a meta-analysis.

BACKGROUND: Published data on the prognostic value of hypoxia-inducible factor-1α (HIF-1α) expression in cervical cancer are conflicting and heterogeneous. We aimed to derive a more precise estimation of them. METHODS: We conducted a clinicopathologic study in 74 patients with early-stage cervical cancer treated through surgery and performed a meta-analysis among patients with cervical cancer of all stages to estimate the prognostic importance of HIF-1α expression for disease-free survival (DFS) and overall survival (OS). Expression of HIF-1α was evaluated through immunohistochemistry. RESULTS: A positive nuclear expression of HIF-1α was found in 94.6% of all specimens. There were significant associations between HIF-1α expression and International Federation of Gynecology and Obstetrics stage (P = 0.024), tumor size (P = 0.003), and anemia (P = 0.010), respectively. Log-rank tests revealed significant correlations between HIF-1α expression, International Federation of Gynecology and Obstetrics stages, tumor grade, tumor size and DFS/OS, respectively. The multivariate Cox regression analyses revealed HIF-1α overexpression and high tumor grade to be independent predictors for impaired DFS (HIF-1α overexpression: hazard ratio [HR], 2.67; 95% confidence interval [CI], 1.10-6.47; high tumor grade: HR, 5.56; 95% CI, 1.47-21.13) and OS (HIF-1α overexpression: HR, 2.57; 95% CI, 1.06-6.23; high tumor grade: HR, 6.23; 95% CI, 1.49-25.97). The results of 10 studies indicated that HIF-1α overexpression predicted poor DFS (HR, 1.98; 95% CI, 1.22-3.21) and OS (HR, 2.58; 95% CI, 1.86-3.56) for cervical cancer. CONCLUSIONS: The present clinicopathologic study and meta-analysis showed that HIF-1α overexpression is associated with poor survival of cervical cancer and emphasized the importance of HIF-1α as a predictor for cervical cancer.

Three-dimensional hidden phase probed by in-plane magnetotransport in kagome metal CsV3Sb5 thin flakes.

Transition metal compounds with kagome structure have been found to exhibit a variety of exotic structural, electronic, and magnetic orders. These orders are competing with energies very close to each other, resulting in complex phase transitions. Some of the phases are easily observable, such as the charge density wave (CDW) and the superconducting phase, while others are more challenging to identify and characterize. Here we present magneto-transport evidence of a new phase below ~ 35 K in the kagome topological metal CsV3Sb5 (CVS) thin flakes between the CDW and the superconducting transition temperatures. This phase is characterized by six-fold rotational symmetry in the in-plane magnetoresistance (MR) and is connected to the orbital current order in CVS. Furthermore, the phase is characterized by a large in-plane negative magnetoresistance, which suggests the existence of a three-dimensional, magnetic field-tunable orbital current ordered phase. Our results highlight the potential of magneto-transport to reveal the interactions between exotic quantum states of matter and to uncover the symmetry of such hidden phases.

Prognostic significance of cyclooxygenase-2 in cervical cancer: a meta-analysis.

Published data on the prognostic value of cyclooxygenase-2 (COX-2) overexpression in cervical cancer are conflicting and heterogeneous. We performed a meta-analysis to more precisely estimate its prognostic significance. The pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the effects. Twenty-three studies with 1,477 cervical cancer patients were selected to evaluate the association between COX-2 and overall survival (OS), disease-free survival (DFS), response to chemoradiation (RC) and clinicopathological parameters. High COX-2 expression predicted poor OS (HR: 2.53, 95% CI: 1.54-4.18), DFS (HR: 2.41, 95% CI: 1.58-3.69) and RC (OR: 3.03, 95% CI: 1.97-4.64). Subgroup analyses showed that COX-2 overexpression was related significantly with poor OS in patients treated by chemoradiation or surgery, and in patients with squamous cell carcinoma, respectively. Besides, COX-2 overexpression was related significantly with poor DFS in chemoradiation subgroup. Furthermore, COX-2 overexpression was associated with poor RC in patients who received "FP" regimen or "P" regimen. Additionally, there were significant associations between COX-2 expression and all clinicopathological parameters except tumor grade. The pooled ORs (95% CI) were as follows: 1.49 (1.09-2.04) for age, 1.77 (1.22-2.56) for lymph node metastasis, 1.04 (0.74-1.47) for tumor grade, 1.71 (1.12-2.64) for tumor size, 2.38 (1.28-4.45) for FIGO stage, 3.96 (2.32-6.77) for histological type, 2.45(1.10-5.42) for parametrical involvement. This meta-analysis indicated that COX-2 overexpression might be an unfavorable prognostic and a chemoradiation resistance predictive factor for cervical cancer; it could potentially help to stratify patients further in clinical treatment.

Recent advances in luminescence and aptamer sensors based analytical determination, adsorptive removal, degradation of the tetracycline antibiotics, an overview and outlook.

Tetracycline antibiotics (TCs), one of the important antibiotic groups, have been widely used in human and veterinary medicines. Their residues in foodstuff, soil and sewage have caused serious threats to food safety, ecological environment and human health. Here, we reviewed the potential harms of TCs residues to foodstuff, environment and human beings, discussed the luminescence and aptamer sensors based analytical determination, adsorptive removal, and degradation strategies of TCs residues from a recent 5-year period. The advantages and intrinsic limitations of these strategies have been compared and discussed, the potential challenges and opportunities in TCs residues degradation have also been deliberated and explored.

Prominent Josephson tunneling between twisted single copper oxide planes of Bi2Sr2-xLaxCuO6+y.

Josephson tunneling in twisted cuprate junctions provides a litmus test for the pairing symmetry, which is fundamental for understanding the microscopic mechanism of high temperature superconductivity. This issue is rekindled by experimental advances in van der Waals stacking and the proposal of an emergent d+id-wave. So far, all experiments have been carried out on Bi2Sr2CaCu2O8+x (Bi-2212) with double CuO2 planes but show controversial results. Here, we investigate junctions made of Bi2Sr2-xLaxCuO6+y (Bi-2201) with single CuO2 planes. Our on-site cold stacking technique ensures uncompromised crystalline quality and stoichiometry at the interface. Junctions with carefully calibrated twist angles around 45° show strong Josephson tunneling and conventional temperature dependence. Furthermore, we observe standard Fraunhofer diffraction patterns and integer Fiske steps in a junction with a twist angle of 45.0±0.2°. Together, these results pose strong constraints on the d or d+id-wave pairing and suggest an indispensable isotropic pairing component.

Giant electrically tunable magnon transport anisotropy in a van der Waals antiferromagnetic insulator.

Anisotropy is a manifestation of lowered symmetry in material systems that have profound fundamental and technological implications. For van der Waals magnets, the two-dimensional (2D) nature greatly enhances the effect of in-plane anisotropy. However, electrical manipulation of such anisotropy as well as demonstration of possible applications remains elusive. In particular, in-situ electrical modulation of anisotropy in spin transport, vital for spintronics applications, has yet to be achieved. Here, we realized giant electrically tunable anisotropy in the transport of second harmonic thermal magnons (SHM) in van der Waals anti-ferromagnetic insulator CrPS4 with the application of modest gate current. Theoretical modeling found that 2D anisotropic spin Seebeck effect is the key to the electrical tunability. Making use of such large and tunable anisotropy, we demonstrated multi-bit read-only memories (ROMs) where information is inscribed by the anisotropy of magnon transport in CrPS4. Our result unveils the potential of anisotropic van der Waals magnons for information storage and processing.

Four polymorphisms of the CAPN 10 gene and their relationship to polycystic ovary syndrome susceptibility: a meta-analysis.

OBJECTIVE: To investigate the association between CAPN 10 gene polymorphism and polycystic ovary syndrome (PCOS) susceptibility. DESIGN: Meta-analysis of published case-control studies of four single nucleotide polymorphisms (SNPs) in CAPN 10 and PCOS susceptibility. PATIENTS: Women with PCOS. MEASUREMENTS: Odds ratios (ORs) and 95% confidence intervals (CIs) for heterozygous, homozygous, dominant model, recessive model and allele. RESULTS: A total of 11 studies were involved in the meta-analysis. UCSNP-63 was significantly associated with PCOS, with homozygous carriers (TT vs CC: OR = 0·64; 95% CI: 0·45-0·90) and recessive model (TT vs CC and CT: OR = 0·64; 95% CI: 0·45-0·90) being protective factors. In addition, UCSNP-19 was significantly associated with PCOS, with recessive model (ins/ins vs del/del and del/ins: OR = 0·72, 95% CI: 0·59-0·88) and insert allele (ins vs del: OR = 0·85, 95% CI: 0·76-0·96) being protective factors, while heterozygous carriers (del/ins vs del/del: OR = 1·56, 95% CI: 1·24-1·94) and deletion allele (del vs ins: OR = 1·18, 95% CI: 1·04-1·32) being risk factors. However, no significant associations were found between UCSNP-44, -43 and PCOS. Moreover, the results of the Rotterdam criteria subgroup analysis were similar with that of overall analysis. CONCLUSIONS: This is the first report on the association between CAPN 10 UCSNP-63 and PCOS in genotype, with homozygous carriers and recessive model being protective factors. Additionally, insert allele and recessive model of UCSNP-19 are protective factors, while deletion allele and heterozygous genotype are risk factors for PCOS development.

CYP1A1 Ile462Val is a risk factor for ovarian cancer development.

Published data on the association between CYP1A1 gene polymorphism and ovarian cancer risk are conflicting and heterogeneous. To derive a more precise estimation of the relationship, a meta-analysis was performed. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were performed for heterozygous, homozygous, dominant model, recessive model and allele, respectively. A total of 15 case-control studies were identified, among which, 13 studies (1815 cases and 3501 controls) were eligible for CYP1A1 Ile(462)Val and nine studies (2495 cases and 3553 controls) were eligible for CYP1A1 Msp1. Overall, Ile(462)Val was significantly associated with ovarian cancer, with homozygous carriers (Val/Val vs. Ile/Ile: OR=2.64; 95% CI: 1.63-4.28) and recessive model (Val/Val vs. Ile/Ile and Ile/Val: OR=2.30; 95% CI: 1.45-3.65) being risk factors for ovarian cancer development. In the subgroup analysis by ethnicity, significantly increased risks were found for Caucasians (homozygous carriers: OR=4.91; 95% CI: 2.07-11.66; recessive model: OR=3.26; 95% CI: 1.41-7.50) and Asians (homozygous carriers: OR=3.06; 95% CI: 1.48-6.33; recessive model: OR=2.75; 95% CI: 1.40-5.41; Val allele: OR=1.67; 95% CI: 1.19-2.35). However, no significant associations were found between Msp1 and ovarian cancer in the overall analyses or the subgroup analyses by ethnicity. This meta-analysis denotes the importance for in-depth research regarding of gene-gene, gene-environment interactions, race-specific and histological subtypes specific to obtain a more conclusive response about the function of CYP1A1 in ovarian cancer.

How do El Niño Southern Oscillation (ENSO) and local meteorological factors affect the incidence of seasonal influenza in New York state.

Background: Research is lacking in examining how multiple climate factors affect the incidence of seasonal influenza. We investigated the associations between El Niño Southern Oscillation (ENSO), meteorological factors, and influenza incidence in New York State, United States. Method: We collected emergency department visit data for influenza from the New York State Department of Health. ENSO index was obtained from the National Oceanic and Atmospheric Administration. Meteorological factors, Google Flu Search Index (GFI), and Influenza-like illness (ILI) data in New York State were also collected. Wavelet analysis was used to quantitatively estimate the coherence and phase difference of ENSO, temperature, precipitation, relative humidity, and absolute humidity with emergency department visits of influenza in New York State. Generalized additive models (GAM) were employed to examine the exposure-response relationships between ENSO, weather, and influenza. GFI and ILI data were used to simulate synchronous influenza visits. Results: The influenza epidemic in New York State had multiple periodic and was primarily on the 1-year scale. The incidence of influenza closely followed the low ENSO index by an average of two months, and the lag period of ENSO on influenza was shorter during 2015-2018. Low temperature in the previous 2 weeks and low absolute humidity in the prior week were positively associated with influenza incidence in New York State. We found an l-shaped association between ENSO index and influenza, a parabolic relationship between temperature in the previous two weeks and influenza, and a linear negative association between absolute humidity in the previous week and influenza. The simulation models including GFI and ILI had higher accuracy for influenza visit estimation. Conclusions: Low ENSO index, low temperature, and low absolute humidity may drive the influenza epidemics in New York State. The findings can help us deepen the understanding of the climate-influenza association, and help to develop an influenza forecasting model.

4,4'-Bipyridine-4-(p-toluene-sulfonamido)-benzoic acid (1/2).

In the title compound, C(14)H(13)NO(4)S·0.5C(10)H(8)N(2), the two benzene rings are nearly perpendicular to each other [dihedral angle = 83.21 (10)°]. The bipyridine mol-ecule is centrosymmetric, the mid-point of the C-C bond linking the pyridine rings being located on an inversion center. Inter-molecular N-H⋯O and O-H⋯N hydrogen bonds and weak inter-molecular C-H⋯O hydrogen bonds are present in the crystal structure.